title: Site-specific structural constraints on protein sequence evolutionary divergence: local packing density versus solvent exposure.
abstract: Protein sequences evolve under selection pressures imposed by functional and biophysical requirements, resulting in site-dependent rates of amino acid substitution. Relative solvent accessibility (RSA) and local packing density (LPD) have emerged as the best candidates to quantify structural constraint. Recent research assumes that RSA is the main determinant of sequence divergence. However, it is not yet clear which is the best predictor of substitution rates. To address this issue, we compared RSA and LPD with site-specific rates of evolution for a diverse data set of enzymes. In contrast with recent studies, we found that LPD measures correlate better than RSA with evolutionary rate. Moreover, the independent contribution of RSA is minor. Taking into account that LPD is related to backbone flexibility, we put forward the possibility that the rate of evolution of a site is determined by the ease with which the backbone deforms to accommodate mutations.
authors.affiliation: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, HsinChu, Taiwan, ROC.
authors.forename: So-Wei
authors.initials: SW
authors.lastname: Yeh
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Liu
authors.forename: Sung-Huan
authors.initials: SH
authors.lastname: Yu
authors.forename: Chien-Hua
authors.initials: CH
authors.lastname: Shih
authors.forename: Jenn-Kang
authors.initials: JK
authors.lastname: Hwang
authors.forename: Julian
authors.initials: J
authors.lastname: Echave
mesh_terms: D019943:Amino Acid Substitution; D004798:Enzymes / Q000737:chemistry*; D019143:Evolution, Molecular; D009154:Mutation; D011487:Protein Conformation; D012997:Solvents; D013329:Structure-Activity Relationship
chemical_list: D004798:Enzymes; D012997:Solvents
keywords: contact number; local packing density; protein evolution; protein structure; relative solvent accessibility; site-specific evolutionary rate; weighted contact number